A5038367858- Liver physiology and pathology
- Pancreatic function and diabetes
- Pancreatic and Hepatic Oncology Research
- Drug Transport and Resistance Mechanisms
- Liver Disease Diagnosis and Treatment
- Drug-Induced Hepatotoxicity and Protection
- Cholangiocarcinoma and Gallbladder Cancer Studies
- Hepatitis B Virus Studies
- Genetics and Neurodevelopmental Disorders
- Epigenetics and DNA Methylation
- Organ Transplantation Techniques and Outcomes
- Liver Disease and Transplantation
- Biosensors and Analytical Detection
- Pediatric Hepatobiliary Diseases and Treatments
- Cancer-related gene regulation
- Wnt/β-catenin signaling in development and cancer
- Phagocytosis and Immune Regulation
- Genomics, phytochemicals, and oxidative stress
- Hepatitis C virus research
- Bioactive Compounds and Antitumor Agents
- Cancer, Hypoxia, and Metabolism
- Pharmacogenetics and Drug Metabolism
- SARS-CoV-2 detection and testing
- T-cell and Retrovirus Studies
- Spaceflight effects on biology
Brigham and Women's Hospital
2015-2024
Harvard University
2015-2024
University of Kansas Medical Center
2010-2022
Massachusetts General Hospital
2016
Memorial Sloan Kettering Cancer Center
2016
University of Kansas
2012-2014
Acetaminophen (APAP) overdose results in acute liver failure and has limited treatment options. Previous studies show that stimulating regeneration is critical for survival after APAP overdose, but the mechanisms remain unclear. In this study, we identified major signaling pathways involved APAP-induced injury using a novel incremental dose model. Liver were studied C57BL/6 mice treated with either 300 mg/kg (APAP300) or 600 (APAP600) APAP. Mice APAP300 developed extensive robust...
Hepatocyte nuclear factor 4 alpha (HNF4α), the master regulator of hepatocyte differentiation, has been recently shown to inhibit proliferation by way unknown mechanisms. We investigated mechanisms HNF4α-induced inhibition using a novel tamoxifen (TAM)-inducible, hepatocyte-specific HNF4α knockdown mouse model. Hepatocyte-specific deletion in adult mice resulted increased proliferation, with significant increase liver-to-body-weight ratio. determined global gene expression changes Illumina...
Abstract The liver plays a central role in metabolism, protein synthesis and detoxification. It possesses unique regenerative capacity upon injury. While many factors regulating cellular proliferation during repair have been identified, the mechanisms by which injured maintains vital functions prior to tissue recovery are unknown. Here, we identify new phase of functional compensation following acute injury that occurs proliferation. By coupling single-cell RNA-seq with situ transcriptional...
Farnesoid X receptor (FXR), the primary bile acid-sensing nuclear receptor, also plays a role in stimulation of liver regeneration. Whole body deletion FXR results significant inhibition regeneration after partial hepatectomy (PHX). is expressed and intestines, recent reports indicate that regulates distinct set genes tissue-specific manner. These data raise question about relative contribution hepatic intestinal regulation We studied PHX hepatocyte-specific knockout (hepFXR-KO) mice over...
Hepatocyte nuclear factor-4α (HNF4α) is known as the master regulator of hepatocyte differentiation. Recent studies indicate that HNF4α may inhibit proliferation via mechanisms have yet to be identified. Using a knockdown mouse model based on delivery inducible Cre recombinase an adeno-associated virus 8 viral vector, we investigated role in regulation proliferation. Hepatocyte-specific deletion resulted increased Global gene expression analysis showed majority downregulated genes were...
Bile acids play a critical role in liver injury and regeneration, but their acetaminophen (APAP)-induced is not known. We tested the effect of bile acid modulation on APAP hepatotoxicity using C57BL/6 mice, which were fed normal diet, 2% cholestyramine (CSA)-containing diet for depletion, or 0.2% cholic (CA)-containing 1 week before treatment with 400 mg/kg APAP. CSA-mediated depletion resulted significantly higher delayed regeneration after treatment. In contrast, CA supplementation...
Abstract Background and Aims Hepatocyte nuclear factor 4 alpha (HNF4α) is indispensable for hepatocyte differentiation critical maintaining liver health. Here, we demonstrate that loss of HNF4α activity a crucial step in the pathogenesis chronic diseases (CLDs) lead to development HCC. Approach Results We developed an target gene signature, which can accurately determine activity, performed exhaustive silico analysis using hierarchical K‐means clustering, survival, rank‐order 30 independent...
Hepatocellular carcinoma (HCC) is the most common hepatic malignancy and third leading cause of cancer related deaths. Previous studies have implicated bile acids in pathogenesis HCC, but mechanisms are not known. We investigated HCC tumor promotion by diethylnitrosamine (DEN)-initiation-cholic acid (CA)-induced protocol mice. The data show that 0.2% CA treatment resulted threefold increase number size DEN-induced liver tumors. All tumors observed DEN-treated mice were well-differentiated...
Overdose of acetaminophen (APAP) results in acute liver failure. We have investigated the role a posttranslational modification proteins called O-GlcNAcylation, where O-GlcNAc transferase (OGT) adds and O-GlcNAcase (OGA) removes single β-D-N-acetylglucosamine (O-GlcNAc) moiety, pathogenesis APAP-induced injury. Hepatocyte-specific OGT knockout mice (OGT KO), which reduced wild-type (WT) controls were treated with 300 mg/kg APAP development injury was studied over time course from 0 to 24 h....
Despite a few global regions with increased incidence, cancers of the biliary tract remain rare entity. Cholangiocarcinoma has been referred to as an ‘orphan’ cancer, given its relative infrequency in Western population.
Under chronic stress, cells must balance competing demands between cellular survival and tissue function. In metabolic dysfunction-associated steatotic liver disease (MASLD, formerly NAFLD/NASH), hepatocytes cooperate with structural immune to perform crucial metabolic, synthetic, detoxification functions despite nutrient imbalances. While prior work has emphasized stress-induced drivers of cell death, the dynamic adaptations surviving their functional repercussions remain unclear. Namely,...
Hepatocyte nuclear factor 4 alpha (HNF4α) is known as the master regulator of hepatic differentiation, which regulates over 60% hepatocyte specific genes. Recent studies including this (Walesky et al. Am J Physiol Gastrointest Liver Physiol. 304:G26-37, 2013) demonstrated that HNF4α also inhibits proliferation via repression pro-mitogenic In study knockout mice were generated using 2-3 month old HNF4α-floxed treated with Cre recombinase under Major Urinary Protein promoter delivered in AAV8...
Fluorescence-based assays provide sensitive and adaptable methods for point of care testing, environmental monitoring, studies protein abundance activity, a wide variety additional applications. Currently, their utility in remote low-resource environments is limited by the need technically complicated or expensive instruments to read out fluorescence signal. Here we describe Genes Space Fluorescence Viewer (GiS Viewer), portable, durable viewer rapid molecular assay readout that can be used...
Abstract Fluorescence-based assays provide sensitive and adaptable methods for point of care testing, environmental monitoring, studies protein abundance activity, a wide variety additional applications. Currently, their utility in remote low-resource environments is limited by the need technically complicated or expensive instruments to read out fluorescence signal. Here we describe Genes Space Fluorescence Viewer (GiS Viewer), portable, durable viewer rapid molecular assay readout that can...
Bile acids are known to play significant role in liver homeostasis. However, the of bile pathogenesis acetaminophen (APAP)‐induced acute failure (ALF) is not known. Here we report that depletion using cholestyramine (CSA), a acid sequestering resin, increases susceptibility C57BL6 mice APAP‐induced hepatotoxicity. were fed either normal diet or 2% CSA containing for 1 week, treated with 400 mg/kg APAP (ip) and analyzed over time course 0 24 hr. The CSA‐fed developed rapid higher injury after...
The utility of in vitro human disease models is mainly dependent on the availability and functional maturity tissue-specific cell types. We have previously screened for identified small molecules that can enhance hepatocyte function vitro. Here, we characterize effects one hits, FH1, primary hepatocytes vitro, also vivo a zebrafish model. Furthermore, conducted an analogue screen to establish structure-activity relationship FH1. performed affinity-purification proteomics NQO2 be potential...
Abstract Drug metabolism leads to biotransformations of pharmaceutical substances that alter drug efficacy, toxicity, as well interactions. Modeling these processes ex vivo stands greatly accelerate our capacity develop safe and efficacious drugs formulations. Recognizing the liver primary site metabolism, here we report a novel whole-tissue screening platform enabled modeling hepatic tracking hepatotoxic metabolites. We applied system for characterization acetaminophen (APAP) identified...
Previous studies from our laboratory using conditional knockout mice and functional genomics have shown that HNF4α inhibits hepatocyte proliferation deletion of promotes DEN‐induced hepatic tumors in mice. To further delineate the role tumorigenesis, we performed RNA‐seq analysis on HCCs obtained HNF4α‐null, WT, normal mouse liver tissue. A total 2152 genes were differentially expressed HCC HNF4α‐null Comparative data with ChIP‐seq revealed a novel gene signature for lacking HNF4α. This 322...
Acetaminophen (APAP) overdose is the major cause of acute liver failure (ALF) with limited treatment options. Liver regeneration a critical determinant survival after APAP and regenerative therapies hold great potential to treat APAP‐induced ALF. However, mechanisms following are not known. We did comprehensive analysis pathways involved in using novel incremental dose model “regenerative” (300 mg/kg, APAP300) “non‐regenerative” (600 APAP600) mice. Stimulation at APAP300 resulted complete...